Disease Progression of Data-Driven Subtypes of Parkinson's Disease: 5-Year Longitudinal Study from the Early Parkinson's disease Longitudinal Singapore (PALS) Cohort.

Background: The detailed trajectory of data-driven subtypes in Parkinson's disease (PD) within Asian cohorts remains undisclosed. Objective: To evaluate the motor, non-motor symptom (NMS) progression among the data-driven PD clusters. Methods: In this 5-year longitudinal study, NMS scale (NMSS), Hospital Anxiety Depression Scale (HADS), and Epworth sleepiness scale (ESS) were carried out annually to monitor NMS progression. H& Y staging scale, MDS-UPDRS part III motor score, and postural instability gait difficulty (PIGD) score were assessed annually to evaluate disease severity and motor progression. Five cognitive standardized scores were used to assess detailed cognitive progression. Linear mixed model was performed to assess the annual progression rates of the longitudinal outcomes. Results: Two hundred and six early PD patients, consisting of 43 patients in cluster A, 98 patients in cluster B and 65 subjects in cluster C. Cluster A (severe subtype) had significantly faster progression slope in NMSS Domain 3 (mood/apathy) score (p = 0.01), NMSS Domain 4 (perceptual problems) score (p = 0.02), NMSS Domain 7 (urinary) score (p = 0.03), and ESS Total Score (p = 0.04) than the other two clusters. Cluster A also progressed significantly in PIGD score (p = 0.04). For cognitive outcomes, cluster A deteriorated significantly in visuospatial domain (p = 0.002), while cluster C (mild subtype) deteriorated significantly in executive domain (p = 0.04). Conclusions: The severe cluster had significantly faster progression, particularly in mood and perceptual NMS domains, visuospatial cognitive performances, and postural instability gait scores. Our findings will be helpful for clinicians to stratify and pre-emptively manage PD patients by developing intervention strategies to counter the progression of these domains.

Outcomes after deep brain stimulation for elderly versus non-elderly patients with Parkinson's disease.

INTRODUCTION: The decision to offer deep brain stimulation (DBS) to elderly patients with Parkinson's disease (PD) presents challenges due to higher perceived risks and uncertain long-term benefits. Here, we aimed to compare the outcomes after DBS for elderly versus non-elderly patients with PD. METHODS: We analyzed data from our institutional cohort and retrieved publicly available data through a systematic review. The exposure was age at DBS electrode insertion, which was defined as elderly (≥70 years old) and non-elderly (<70 years old). The outcomes examined were changes in the Movement Disorders Society-Parkinson's Disease Rating Scale (MDS-UPDRS) or UPDRS part III total score, levodopa-equivalent daily dose (LEDD), and adverse events. RESULTS: The included studies and our cohort comprised a total of 527 patients, with 111 (21.1 %) classified as elderly. There was no statistically significant difference in the change in MDS-UPDRS or UPDRS part III total score and generally no statistically significant difference in the change in LEDD between the elderly and non-elderly patients. Elderly patients had a higher incidence of wound infection (elderly 5.4 % vs non-elderly 1.9 %; p = 0.087) and inadequate wound healing (elderly 3.6 % vs non-elderly 1.4 %; p = 0.230), but this difference was not statistically significant. There was no significant difference in the incidence of mortality (elderly 0 % vs non-elderly 0 %; p = 1.000), stroke (elderly 0 % vs non-elderly 0.2 %; p = 1.000), and cognitive decline between the age groups. CONCLUSIONS: Notwithstanding the trend towards a higher risk of wound infection and inadequate wound healing, elderly patients have similar motor outcomes and levels of PD medication reduction as non-elderly patients after DBS for PD. Hence, age should not be used as the sole criterion for determining eligibility for DBS, and the decision to offer DBS to elderly patients should be personalized and made in a multidisciplinary setting, taking into consideration patient- and disease-related factors.

Parkinson's disease genome-wide association study-linked PARK16 variant is associated with a lower risk of cognitive impairment: A 4-year observational study.

BACKGROUND AND PURPOSE: A genome-wide association study-linked variant (PARK16 rs6679073) modulates the risk of Parkinson's disease (PD). We postulate that there may be differences in clinical characteristics between PARK16 rs6679073 carriers and noncarriers. In a prospective study, we investigate the clinical characteristics between PARK16 rs6679073 A allele carriers and noncarriers over 4 years. METHODS: A total of 204 PD patients, comprising 158 PARK16 rs6679073 A allele carriers and 46 noncarriers, were recruited. All patients underwent motor and nonmotor symptom and cognitive assessments yearly over 4 years. RESULTS: PARK16 rs6679073 carriers were less likely to have mild cognitive impairment (MCI) compared to noncarriers at both baseline (48.1% vs. 67.4%, p = 0.027) and 4-year follow-up (29.3% vs. 58.6%, p = 0.007). CONCLUSIONS: PD PARK16 rs6679073 carriers had significantly lower frequency of MCI in a 4-year follow-up study, suggesting that the variant may have a neuroprotective effect on cognitive functions.

Identifying clinical features and blood biomarkers associated with mild cognitive impairment in Parkinson disease using machine learning.

BACKGROUND AND PURPOSE: A broad list of variables associated with mild cognitive impairment (MCI) in Parkinson disease (PD) have been investigated separately. However, there is as yet no study including all of them to assess variable importance. Shapley variable importance cloud (ShapleyVIC) can robustly assess variable importance while accounting for correlation between variables. Objectives of this study were (i) to prioritize the important variables associated with PD-MCI and (ii) to explore new blood biomarkers related to PD-MCI. METHODS: ShapleyVIC-assisted variable selection was used to identify a subset of variables from 41 variables potentially associated with PD-MCI in a cross-sectional study. Backward selection was used to further identify the variables associated with PD-MCI. Relative risk was used to quantify the association of final associated variables and PD-MCI in the final multivariable log-binomial regression model. RESULTS: Among 41 variables analysed, 22 variables were identified as significantly important variables associated with PD-MCI and eight variables were subsequently selected in the final model, indicating fewer years of education, shorter history of hypertension, higher Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor score, higher levels of triglyceride (TG) and apolipoprotein A1 (ApoA1), and SNCA rs6826785 noncarrier status were associated with increased risk of PD-MCI (p < 0.05). CONCLUSIONS: Our study highlighted the strong association between TG, ApoA1, SNCA rs6826785, and PD-MCI by machine learning approach. Screening and management of high TG and ApoA1 levels might help prevent cognitive impairment in early PD patients. SNCA rs6826785 could be a novel therapeutic target for PD-MCI. ShapleyVIC-assisted variable selection is a novel and robust alternative to traditional approaches for future clinical study to prioritize the variables of interest.

Plasma Neurofilament Light Concentration Is Associated with Diffusion-Tensor MRI-Based Measures of Neurodegeneration in Early Parkinson's Disease.

BACKGROUND: Neurofilament light is a marker of axonal degeneration, whose measurement from peripheral blood was recently made possible by new assays. OBJECTIVE: We aimed to determine whether plasma neurofilament light chain (NfL) concentration reflects brain white matter integrity in patients with early Parkinson's disease (PD). METHODS: 137 early PD patients and 51 healthy controls were included. Plasma NfL levels were measured using ultrasensitive single molecule array. 3T MRI including diffusion tensor imaging was acquired for voxelwise analysis of association between NfL and both fractional anisotropy (FA) and mean diffusivity (MD) in white matter tracts and subcortical nuclei. RESULTS: A pattern of brain microstructural changes consistent with neurodegeneration was associated with increased plasma NfL in most of the frontal lobe and right internal capsule, with decreased FA and increased MD. The same clusters were also associated with poorer global cognition. A significant cluster in the left putamen was associated with increased NfL, with a significantly greater effect in PD than controls. CONCLUSION: Plasma NfL may be associated with brain microstructure, as measured using diffusion tensor imaging, in patients with early PD. Higher plasma NfL was associated with a frontal pattern of neurodegeneration that also correlates with cognitive performance in our cohort. This may support a future role for plasma NfL as an accessible biomarker for neurodegeneration and cognitive dysfunction in PD.

Poor sleep quality is associated with fatigue and depression in early Parkinson's disease: A longitudinal study in the PALS cohort.

Background: Sleep disorders are common in Parkinson's disease (PD). However, the longitudinal relationship between sleep quality and the other non-motor symptoms of PD has not been well characterized, especially in early PD. Objective: To explore the value of baseline sleep quality in predicting the progression of other non-motor symptoms in early PD. Methods: 109 early PD patients were recruited to the study. Patients were stratified into good and poor sleepers using the Pittsburgh Sleep Quality Index (PSQI). Assessments performed at baseline and 1 year follow-up included the Epworth Sleepiness Scale, Fatigue Severity Scale, Non-Motor Symptom Scale, Geriatric Depression Scale, Hospital Anxiety and Depression Scale, Apathy Scale, Montreal Cognitive Assessment and detailed neuropsychological assessments. Multivariable linear regression was performed at baseline to investigate differences in clinical scores between poor and good sleepers, while multivariable regression models were used to investigate associations between sleep quality and progression of test scores at 1 year follow-up. Results: 59 poor sleepers and 50 good sleepers were identified. At baseline, poor sleepers had greater HADS anxiety scores (p = 0.013) [2.99 (95% CI 2.26, 3.73)] than good sleepers [1.59 (95% CI 0.75, 2.42)]. After 1 year, poor sleepers had greater fatigue (FSS scores +3.60 as compared to -2.93 in good sleepers, p = 0.007) and depression (GDS scores +0.42 as compared to -0.70, p = 0.006). Conclusion: This study shows a longitudinal association between sleep quality, fatigue, and depression in early PD patients, independent of medication effect and disease severity, this may support the hypothesis that a common serotonergic pathway is implicated in these non-motor symptoms.

Longitudinal Studies of Sleep Disturbances in Parkinson's Disease.

PURPOSE OF REVIEW: Sleep disorders are among the most common non-motor symptoms in Parkinson's disease (PD). Recent longitudinal studies of sleep in PD have utilized validated sleep questionnaires and video-polysomnography performed over multiple time points. This review summarizes existing longitudinal studies focusing on the prevalence, associations, and changes of sleep disorders in PD over time, as well as the methodologies used in these studies. RECENT FINDINGS: Fifty-three longitudinal studies of sleep in PD were identified: excessive daytime sleepiness, insomnia, obstructive sleep apnea, rapid eye movement sleep behavior disorder (RBD), restless legs syndrome, and shift work disorder were studied in addition to other studies that had focused on either multiple sleep disorders or broadly on sleep disorders as a whole. The prevalence of sleep disorders increases over time and are associated particularly with non-motor features of disease. RBD is now considered an established prodromal feature of PD, but other sleep disorders do not clearly increase risk of subsequent PD. Further work is necessary to determine if treatment of sleep disorders in PD alters disease symptom and their progression or reduces PD risk. Longitudinal studies of sleep in PD have demonstrated a high prevalence of sleep disorders that are associated with non-motor features of PD which can increase over time. More work is necessary to determine if treatment of sleep disorders can alter the course of PD.

Biomarker characterization of clinical subtypes of Parkinson Disease.

The biological underpinnings of the PD clusters remain unknown as the existing PD clusters lacks biomarker characterization. We try to identify clinical subtypes of Parkinson Disease (PD) in an Asian cohort and characterize them by comparing clinical assessments, genetic status and blood biochemical markers. A total of 206 PD patients were included from a multi-centre Asian cohort. Hierarchical clustering was performed to generate PD subtypes. Clinical and biological characterization of the subtypes were performed by comparing clinical assessments, allelic distributions of Asian related PD gene (SNCA, LRRK2, Park16, ITPKB, SV2C) and blood biochemical markers. Hierarchical clustering method identified three clusters: cluster A (severe subtype in motor, non-motor and cognitive domains), cluster B (intermediate subtype with cognitive impairment and mild non-motor symptoms) and cluster C (mild subtype and young age of onset). The three clusters had significantly different allele frequencies in two SNPs (Park16 rs6679073 A allele carriers in cluster A B C: 67%, 74%, 89%, p = 0.015; SV2C rs246814 T allele distribution: 7%, 12%, 25%, p = 0.026). Serum homocysteine (Hcy) and C-reactive protein (CRP) levels were also significantly different among three clusters (Mean levels of Hcy and CRP among cluster A B C were: 19.4 ± 4.2, 18.4 ± 5.7, 15.6 ± 5.6, adjusted p = 0.005; 2.5 ± 5.0, 1.5 ± 2.4, 0.9 ± 2.1, adjusted p < 0.0001, respectively). Of the 3 subtypes identified amongst early PD patients, the severe subtype was associated with significantly lower frequency of Park16 and SV2C alleles and higher levels of Hcy and CRP. These biomarkers may be useful to stratify PD subtypes and identify more severe subtypes.

Blood Lipid Biomarkers in Early Parkinson's Disease and Parkinson's Disease with Mild Cognitive Impairment.

BACKGROUND: Lipid biomarkers have potential neuroprotective effects in Parkinson's disease (PD) and there is limited evidence in the field. OBJECTIVE: This study aims to investigate the association between comprehensive blood lipid biomarkers and PD. METHODS: A total of 205 PD patients and 102 non-PD subjects were included from Early Parkinson's disease Longitudinal Singapore (PALS) cohort. We investigated 6 serum lipid biomarkers including total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (Apo A1), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B). PD patients were further classified into mild cognitive impairment (MCI) and normal cognition (NC) subgroups. We conducted a cross-sectionals study to examine the association between lipids and PD and further explored the relationship between lipids and PD-MCI. RESULTS: PD patients had significantly lower level of lipid panel including TC, TG, HDL-C, Apo A1, LDL-C, and Apo B (all p < 0.05). TC, TG, Apo A1, and Apo B levels were independent protective factors (p < 0.05) for PD in the logistic regression model. PD-MCI group had significantly higher mean TC, TG, and Apo A1 levels compared to PD-NC group. Higher TC, TG, and Apo A1 levels were independent risk factors (p < 0.05) for PD-MCI. CONCLUSION: We demonstrated that PD patients had significantly lower levels of lipid biomarkers while PD-MCI patients had higher levels of TC, TG, and Apo A1. TC, TG, and Apo A1 may be useful biomarkers for PD-MCI.

Longitudinal Healthcare Utilization and Costs in Parkinson's Disease: Pre-Diagnosis to 9 Years After.

BACKGROUND: There is currently insufficient long-term data on costs of treatment in patients with Parkinson's disease (PD), which is chronic and progressive, and associated with substantial healthcare costs. Identifying patterns in healthcare utilization and cost may illuminate further discussion on early intervention. OBJECTIVE: To characterize long-term healthcare utilization and costs of PD in newly diagnosed patients managed by movement disorder specialists. METHODS: Using a longitudinal matched-cohort study of linked data from the National Neuroscience Institute Parkinson's disease and Movement Disorder and healthcare administrative databases in Singapore from 2008-2017, we compared healthcare utilization and costs between patients and controls matched on age, sex, race, and Charlson Comorbidity Index score. RESULTS: 1,162 patients met study inclusion criteria and 1,157 matched controls were identified. The total mean annual healthcare cost (at 2017 costs) was significantly increased in patients compared to controls from years 1-9 post-diagnosis. The increased cost was observed 2 years before diagnosis (USD2322 vs. 2052; p < 0.001). Mean annual cost attributable to PD increased from USD1854 at 1-year post-diagnosis to USD2652 at 9 years. Over 9 years, average costs were significantly higher across all domains of healthcare utilization except primary care-cost of intermediate and long-term care was increased by a factor of 2.5, specialist care by 2.3, emergency department visits by 1.6, and hospital admissions by 1.3. CONCLUSION: PD results in higher healthcare utilization and costs. Pre-diagnosis increase in healthcare utilization observed in patients supports the presence of prodromal PD symptoms and may present an opportunity for early diagnosis.

Longitudinal Study of SNCA Rep1 Polymorphism on Executive Function in Early Parkinson's Disease.

The alpha-synuclein gene promoter (SNCA-Rep1) is associated with Parkinson's disease (PD), but its relationship with performance across individual cognitive domains in early PD is unknown. This study aims to investigate Rep1 polymorphism and longitudinal change in cognition in early PD. In this longitudinal study, Rep1 allele lengths ("long" and "short") were determined in 204 early PD patients. All participants underwent annual neuropsychological assessments and followed up for 3 years. Linear-mixed model was performed to investigate the association of Rep1 status and longitudinal change in individual cognitive domains. At 3 years, significant decline in executive function was observed in long Rep1 allele carriers vs short allele carriers, controlling for potential confounders. This is the first longitudinal study demonstrating that long Rep1 allele carriers are at higher risk for executive dysfunction in early PD.

Apathy is associated with white matter network disruption and specific cognitive deficits in Parkinson's disease.

BACKGROUND: Apathy is common in Parkinson's disease (PD) but its underlying white matter (WM) architecture is not well understood. Moreover, how apathy affects cognitive functions in PD remains unclear. We investigated apathy-related WM network alterations and the impact of apathy on cognition in the context of PD. METHODS: Apathetic PD patients (aPD), non-apathetic PD patients (naPD), and matched healthy controls (HCs) underwent brain scans and clinical assessment. Graph-theoretical and network-based analyses were used for group comparisons of WM features derived from diffusion spectrum imaging (DSI). Path analysis was used to determine the direct and indirect effects of apathy and other correlates on different cognitive functions. RESULTS: The aPD group was impaired on neural integration measured by global efficiency (p = 0.009) and characteristic path length (p = 0.04), executive function (p < 0.001), episodic memory (p < 0.001) and visuospatial ability (p = 0.02), and had reduced connectivity between the bilateral parietal lobes and between the putamen and temporal regions (p < 0.05). In PD, executive function was directly impacted by apathy and motor severity and indirectly influenced by depression; episodic memory was directly and indirectly impacted by apathy and depression, respectively; conversely, visuospatial ability was not related to any of these factors. Neural integration, though being marginally correlated with apathy, was not associated with cognition. CONCLUSIONS: Our results suggest compromised neural integration and reduced structural connectivity in aPD. Apathy, depression, and motor severity showed distinct impacts on different cognitive functions with apathy being the most influential determinant of cognition in PD.

Stability of MDS-UPDRS Motor Subtypes Over Three Years in Early Parkinson's Disease.

Background: Various classifications have been proposed to subtype Parkinson's disease (PD) based on their motor phenotypes. However, the stability of these subtypes has not been properly evaluated. Objective: The goal of this study was to understand the distribution of PD motor subtypes, their stability over time, and baseline factors that predicted subtype stability. Methods: Participants (n = 170) from two prospective cohorts were included: the Early PD Longitudinal Singapore (PALS) study and the National Neuroscience Institute Movement Disorders Database. Early PD patients were classified into tremor-dominant (TD), postural instability and gait difficulty (PIGD), and indeterminate subtypes according to the Movement Disorder Society's Unified PD Rating Scale (MDS-UPDRS) criteria and clinically evaluated for three consecutive years. Results: At baseline, 60.6% patients were TD, 12.4% patients were indeterminate, and 27.1% patients were PIGD subtypes (p < 0.05). After 3 years, only 62% of patients in TD and 50% of patients in PIGD subtypes remained stable. The mean levodopa equivalent daily dose (LEDD) was higher in the PIGD subtype (276.92 ± 232.91 mg; p = 0.01). Lower LEDD [p < 0.05, odds ratio (OR) 0.99, 95% confidence interval (CI): 0.98-0.99] and higher TD/PIGD ratios (p < 0.05, OR 1.77, 95% CI: 1.29-2.43) were independent predictors of stability of TD subtype with an area under the curve (AUC) of 0.787 (95%CI: 0.669-0.876), sensitivity = 57.8%, and specificity = 89.7%. Conclusion: Only 50-62% of PD motor subtypes as defined by MDS-UPDRS remained stable over 3 years. TD/PIGD ratio and baseline LEDD were independent predictors for TD subtype stability over 3 years.

Subjective cognitive Complaints in early Parkinson's disease patients with normal cognition are associated with affective symptoms.

INTRODUCTION: Subjective cognitive complaints (SCC) and affective symptoms are highly prevalent in Parkinson's Disease (PD). In early PD, SCC prevalence and its affective correlates, using recommended Movement Disorders Society (MDS) Level II Criteria to define the underlying cognitive impairment, has not been previously explored. METHODS: We recruited 121 participants with early PD from two tertiary hospitals in Singapore. The presence of SCC was defined using a Non-Motor Symptoms Scale Domain-5 Score ≥1. Comprehensive neuropsychological testing was conducted with Mild Cognitive Impairment (PD-MCI) defined using recommended MDS Level II Criteria. Affective symptoms were assessed using the Hospital Anxiety Depression Scale (HADS), Geriatric Depression Scale (GDS) and Apathy Scale (AS). Analysis using multivariable linear regression model was performed. RESULTS: In our early PD cohort, SCC prevalence independent of underlying cognitive status was 38.8%. Prevalence of SCC in cognitively impaired and cognitively normal participants was 10.7% and 28.1% respectively (р = 0.241). In cognitively normal PD participants, multivariable linear regression analysis revealed that SCC was significantly associated with anxiety (ß = 0.28, 95% CI = 0.09-0.79, p = 0.014), depression (ß = 0.31, 95% CI = 0.10-0.59, p = 0.006) and apathy (ß = 0.32, 95% CI = 1.15-5.98, p = 0.004). Such an association was not found in cognitively impaired PD participants. CONCLUSION: SCC is highly prevalent even in early PD. Its implications in early PD differ depending on underlying cognitive status. SCC in cognitively impaired participants underestimates the true prevalence of PD-MCI. In contrast, SCC in cognitively normal participants is suggestive of an underlying affective disorder.

Progression of sleep disturbances in Parkinson's disease: a 5-year longitudinal study.

BACKGROUND: Sleep disorders can occur in early Parkinson's disease (PD). However, the relationship between different sleep disturbances and their longitudinal evolution has not been fully explored. OBJECTIVE: To describe the frequency, coexistence, and longitudinal change in excessive daytime sleepiness (EDS), insomnia, and probable REM sleep behavior disorder (pRBD) in early PD. METHODS: Data were obtained from the Parkinson's Progression Markers Initiative (PPMI). EDS, insomnia, and pRBD were defined using the Epworth Sleepiness Scale, MDS-UPDRS Part I sub-item 1.7, and RBD screening questionnaire. RESULTS: 218 PD subjects and 102 controls completed 5 years of follow-up. At baseline, 69 (31.7%) PD subjects reported one type of sleep disturbance, 25 (11.5%) reported two types of sleep disturbances, and three (1.4%) reported all three types of sleep disturbances. At 5 years, the number of PD subjects reporting one, two, and three types of sleep disturbances was 85 (39.0%), 51 (23.4%), and 16 (7.3%), respectively. Only 41(18.8%) patients were taking sleep medications. The largest increase in frequency was seen in insomnia (44.5%), followed by EDS (32.1%) and pRBD (31.2%). Insomnia was the most common sleep problem at any time over the 5-year follow-up. The frequency of sleep disturbances in HCs remained stable. CONCLUSIONS: There is a progressive increase in the frequency of sleep disturbances in PD, with the number of subjects reporting multiple sleep disturbances increasing over time. Relatively a few patients reported multiple sleep disturbances, suggesting that they can have different pathogenesis. A large number of patients were not treated for their sleep disturbances.

Neurological manifestations in COVID-19: a systematic review and meta-analysis.

OBJECTIVE: Following the outbreak of coronavirus 2019 (COVID-19), there is strong evidence of neurological involvement in these patients. We aimed to determine the clinical characteristics of neurological manifestations in COVID-19. METHOD: A systematic review of studies reporting neurological manifestations published between 1 December, 2019 and 11 May, 2020 was performed. Studies were grouped based on neurological manifestation. Pooled analyses of individual patient's clinical characteristics and olfactory and gustatory dysfunction prevalence were performed. RESULTS: Of 486 studies identified, 48 were included. 70 patients with 73 neurological manifestations were reported. 39 (53.4%) patients had stroke, 18 (24.7%) had Guillain-Barré syndrome and variants, 11 (15.1%) had meningitis, encephalitis, encephalopathy, or myelitis, and five (6.8%) had seizures. They had a mean age of 61.9 ± 17.7 years (60.6% male). Neurological disease occurred 8.1 ± 6.8 days from initial symptoms. Average mortality rate was 17.8%. Stroke has a mortality rate of 25.6%. Olfactory and gustatory dysfunction occurred in 59.9% and 57.5%, respectively. CONCLUSIONS: Stroke is the most frequently reported neurological manifestation in COVID-19 and has the highest mortality rate. Neurological manifestations tend to develop one to two weeks after the onset of respiratory disease. There is significant morbidity and mortality associated with COVID-19 neurological manifestations.

SNCA Rep1 microsatellite length influences non-motor symptoms in early Parkinson's disease.

Long alpha-synuclein gene (SNCA) promoter (Rep1) allele-carriers are linked to higher risk for Parkinson's disease (PD) and faster motor progression. Non-motor symptoms including autonomic, neuropsychiatric, and sleep disorders are common in PD. However, the relationship between SNCA Rep1 microsatellite lengths and non-motor symptoms in early PD remains to be elucidated. 171 consecutive early PD patients were recruited from tertiary clinics and genotyped for Rep1. Multivariable regression analyses were performed to examine associations between Rep1 alleles and non-motor outcome scores. Longer Rep1 alleles significantly associated with higher total Non-Motor Symptom Scale (NMSS) scores (p=.006) and Hospital Anxiety and Depression Scale (HADS) depression subscale scores (p=.002), after adjusting for covariates and Bonferroni correction. We demonstrated that SNCA Rep1 allele length influences overall non-motor symptom burden and depression in early PD patients. Further functional studies to evaluate the role of Rep1 in non-dopaminergic systems may unravel new therapeutic targets for non-motor symptoms in PD.

Phenotypic bases of NOTCH2NLC GGC expansion positive neuronal intranuclear inclusion disease in a Southeast Asian cohort.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder associated with GGC repeats of >60 to 500 copies in the 5'-untranslated region of NOTCH2NLC. The clinical and genetic characterization of NIID outside of East Asia remains unknown. We identified twelve patients who underwent genetic testing using long-read sequencing or repeat primed polymerase chain reaction. All were positive for a GGC repeat expansion; the median repeat length was 107 (range 92-138). Ten were Chinese and two of Malay ethnicity. Age at onset ranged from 50 to 69 years. Eight (66.7%) patients had dementia, while four (33.3%) patients were oligosymptomatic, without typical NIID symptoms of dementia, Parkinsonism, or muscle weakness. GGA interruptions within the GGC expansion were present in four patients; the number of GGA interruptions was highest (6.71%) in the patient with the earliest age at onset (50 years). Median plasma neurofilament light level was 47.3 pg/mL in seven patients (range 26-380 pg/mL). The highest level (380 pg/mL) was found in one patient who experienced an encephalitic episode. Overall, we describe a cohort of genetically confirmed NIID patients from Southeast Asia and provide further information that the presence of GGA interruptions within GGC repeat expansions may serve as a potential genetic modifier in NIID.

Corrigendum: Increased Activation of Default Mode Network in Early Parkinson's With Excessive Daytime Sleepiness.

[This corrects the article DOI: 10.3389/fnins.2019.01334.].